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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Interferon regulatory factor 1–Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury
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Interferon regulatory factor 1–Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury

机译：干扰素调节因子1-RAB27A调节细胞外囊泡促进肝脏缺血/再灌注损伤

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摘要

The role and regulators of extracellular vesicle (EV) secretion in hepatic ischemia/reperfusion (IR) injury have not been defined. Rab27a is a guanosine triphosphatase known to control EV release. Interferon regulatory factor 1 (IRF‐1) is a transcription factor that plays an important role in liver IR and regulates certain guanosine triphosphatases. However, the relationships among IRF‐1, Rab27a, and EV secretion are largely unknown. Here, we show induction of IRF‐1 and Rab27a both in vitro in hypoxic hepatocytes and in vivo in warm IR and orthotopic liver transplantation livers. Interferon γ stimulation, IRF‐1 transduction, or IR promoted Rab27a expression and EV secretion. Meanwhile, silencing of IRF‐1 decreased Rab27a expression and EV secretion. Rab27a silencing decreased EV secretion and liver IR injury. Ten putative IRF‐1 binding motifs in the 1,692‐bp Rab27a promoter region were identified. Chromatin immunoprecipitation and electrophoretic mobility shift assay verified five functional IRF‐1 binding motifs, which were confirmed by a Rab27a promoter luciferase assay. IR‐induced EVs contained higher oxidized phospholipids (OxPL). OxPLs on the EV surface activated neutrophils through the toll‐like receptor 4 pathway. OxPL‐neutralizing E06 antibody blocked the effect of EVs and decreased liver IR injury. Conclusion: These findings provide a novel mechanism by which IRF‐1 regulates Rab27a transcription and EV secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. (H epatology 2018;67:1056–1070)
机译：尚未定义肝脏缺血/再灌注（IR）损伤中细胞外囊泡（EV）分泌的作用和调节剂。 Rab27a是众所周知的鸟氨酸三磷酸酶，用于控制EV释放。干扰素调节因子1（IRF-1）是在肝红外发挥重要作用的转录因子，并调节某些鸟苷三磷脂酶。然而，IRF-1，RAB27A和EV分泌之间的关系在很大程度上是未知的。在此，我们在温热的IR和原位肝移植肝脏中显示IRF-1和RAB27A的IRF-1和RAB27A诱导。干扰素γ刺激，IRF-1转导，或IR促进RAB27A表达和EV分泌。同时，IRF-1的沉默减少了RAB27A表达和EV分泌。 Rab27a沉默的沉默和肝红外损伤。鉴定了1,692-BP Rab27A启动子区域中的十个推定的IRF-1结合基序。染色质免疫沉淀和电泳迁移率移位测定验证了五种功能性IRF-1结合基序，其通过Rab27A启动子荧光素酶测定法证实。 IR诱导的EVS含有更高的氧化磷脂（OXPL）。通过Toll样受体4途径在EV表面活化中性粒细胞上的OXPL。 EXPL-中和E06抗体阻断了EVS和肝红外损伤的作用。结论：这些发现提供了一种新机制，IRF-1调节RAB27A转录和EV分泌，导致中性粒细胞和随后的肝脏IR损伤的EXPL活化。 （2018年Hopatology; 67：1056-1070）

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    Yang Mu‐qing; Du Qiang; Goswami Julie; Varley Patrick R.; Chen Bin; Wang Rong‐hua; Morelli Adrian E.; Stolz Donna B.; Billiar Timothy R.; Li Jiyu; Geller David A.;

  • 作者单位

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Center of Biological ImagingUniversity of PittsburghPittsburgh PA;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

    Department of Surgery Shanghai Tenth People's HospitalTenth People's Hospital of Tongji;

    Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical;

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  • 中图分类 消化系及腹部疾病;
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